This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The aim of this project is to evaluate the effects of NR2B-10076 and NR2B-10068 on motor behavior of MPTP parkinsonian monkeys. These compounds are two novel NR2B-selective antagonists of high potency, good brain penetration and prolonged half-life that have never been tested for Parkinson's disease. Specificity of motor effects and lower toxicity of NMDA antagonists are usually sought with the NR2B blockers because NR2B containing NMDA receptors are expressed abundantly throughout the striatum and basal ganglia. Other selective NR2B blockers have shown antiparkinsonian effects in animal models but failed to prove safe or efficacious for clinical trials. CP101,606, a previous generation NR2B antagonist showed clear antiparkinsonian effects in primates, however, it possessed important cardiac toxicity and poor bioavailability. The special interest in the new compounds derives from their properties combining high selectivity and potency for NR2B with the lack of cardiac toxicity (hERG potassium channel blockade) characteristic of this class of NMDA antagonists. NR2B-10076 and NR2B-10068 have a unique structural chemistry that confers an advantageous overall profile. The use of MPTP-treated monkeys, the gold-standard animal model of Parkinsons's disease, permits a thorough evaluation of specific effects of NR2B blockers on parkinsonian motor symptoms.